Intermediate compounds in the synthesis of dehydrocorticosterone



Patented May 27, 1952 INTERMEDIATE COMPOUNDS IN THE SYN- THESIS F DEHYDROCORTICOSTERONE Edward C. Kendall, Rochester, Minn, assignor to Research Corporation, New York, N. Y.,. a cor poration oi New York No Drawing. Application November 21, 1949, Serial No. 128,687

9 Claims. 1.

In my application Serial No. 653,176 filed March 8, 1946, now Patent No. 2,541,074, I described a process for the degradation of the side chain in the l7-position-of compounds derived from desoxycholic acid. The present. application is a continuation-in-part of said application and of my application Serial No. 733,188 filed March 7, 1947 and Serial No. 51,488 filed September 27, 1948, now both abandoned, and relates more particularly to the process disclosed insaid application for degrading the side chain in 17-position by the use of bromosuccinimide.

In particular the present application relatesto the preparation of 3(a) -acyloxy l1 keto 12- bromo 24,24 diphenyl-A -choladienes by the action of N-bromosuccinimide upon 3(a)- acyloxy ll-keto-w-bromo 2424 diphenyl-A cholenes.

In this application I shall use the same numbering of the compounds as in the parent application.

The following specific example is illustrative of the principles of the invention and shows the phcnyl-A -cholene (29) from 3,9-epoxy-11-kcto- 24,24-diphenyl-A -cholene (15) .25.00 g. of 3,9- epoxy-ll-keto 24,24. diphenyl-A -cholene was dissolved in 31 ml. of dry alcohol-free chloroform and 31 ml. of acetic anhydride was added, The reaction mixture was cooled in a Dry Ice-acetone bath and 125 g. of dry hydrogen bromide wa i trcduced. The flask was sealed at Dry Ice temperature and then placed in an ice bath for 17 me. was separated and the organic phase was washed with water, sodium carbonate, and. again with water. The chloroform solution was filtered through sodium sulfate, concentrated in'vacuoto hours. The flask was cooled in a Dry Ice-acetone 1 bath and the solution was poured ontochipped Chloroform was added, the aqueous phasea small volume and diluted with methanol. fl-he crystals which formed were filtered and washed Ca),,=+18-;*:2" (29.1 mg. in 3.00 mlehloroform).

2 v In an her run in which 5.00 g. of 3,9 e oxy-ll- Irate-24,24-diphenyl-A -cholene in 6 ml. of chloreform and 6 mljof acetic anhydride was treated with 27 g. of dry hydrogen bromide under similar conditions except that the product was crystal,- lized from hl roform-petroleum o r th rude yi d was s m wha his e (jl'rop I.-4,32, g. =.69.5 per cent; M. P. 175 176". Crop II.1..14 g.=18 p r nt; M- ,P'. 1 9-171. Crop IIl.--0.20 g.=3 per cent; M. P, 165-169". Aiter rec ystallizi e rops I nd III by dis solvins i a s ll. am unt of benzene, add petroleum ether and con entr 1. s (18.6 per cent) material which melted-at 175-176 was obtained.

3(a) -GG61+G$2l-11-Z Q 13 r mo 24.24 d phenyl E A choiddz'ene (31,) from, 3(a)- (rectory-1.1 Jccto-ZZ-brcmo e 2 ,2 d phfifly cholene (29)..=.9.476 g. (0.015 mole) oi 3(a)- acetoxy llnketoem-bromo 24, 24-diphenyl- A -cholene (M. P. 176=-.177) was dissolved in 100 ml. of purified carbontetrachloride in. a 300 ml. round bottom flask and the solution was heated to boiling. 2.675 g. (0.015 mole) of N- bromosuccinimide was added and the solution was refluxed minutes with the flask in contact with a 200-watt bulb. The solution was cooled to room temperature and 5,0 'g, of sodiumacetate in 100 ml. of glacial acetic acid was added and the solution was concentrated in vacuo to about ml. m1. of glacial acetic acid was added and the solution was concentrated in vacuo toabout 25 m1. and refluxed 30 minutes. The solvent was removed in vacuo and the residue was distributed between benzene and water. The benzene solution was washed wit Water s d u bonate and with water, and filtered through sodium sulrate. After removal o the sol t n v o the residue crystallized from acetone methanol. Yield: 6.82 g... M.-

l'i 0.977 a, M. P. 147 156, After two recrystallizations from acetone-water the second crop of crystals weighed 485 mg. and melted at -171". A sample of the first crop recrystallized four times from, acetone, melted at 179-180".

The product is not pure 3(a) -acetoxy-l1.-ket0- lz bromo 4,24 diph nyl-n i- -choladi n (3.1.) but apparently contains about 20 to 25 per cent of the starting material 3(a)-a.cetoxy-11- kfito -lz-bromo-24,2 4-diphenyl- 4 e-cholene .(29). Compound 31 ca be s p rated from this mixture ytreatment with r mosuccinim de whi h resultsin th introduct on oi bromine at the 21 carbon. -b;.ro r1ine derivative of compound 3 can be sepsratedi -puroiormr diphenyl-A -choladiene The preparation of the 12,21 dibromo compound is as follows: The crude diene (31) obtained from 80 g. ethylene (29) was dissolved in 960 ml. carbon tetrachloride, mixed with 23.52 g. of 96 per cent bromosuccidimide and boiled for 20 minutes over a light bulb, cooled and filtered. The filtrate was brought to almost complete dryness and petroleum ether added. 63.0 g. (70.2

per cent) of crystalline material separated. Re-

crystallization from about 200 ml. hot benzene and 200 ml. hot petroleum etheryielded a first crop of 49.0 g. (54.7 per cent) with E=377 at 325 mu in chloroform and a second crop of 6.6 g.

' (6.9 per cent) with E=364.

3(a) -aceto:cy-11,20-dz7c'eto-12 bromopregnane form. .The reaction mixture was cooled in a (32))rom 3(a) -acetoa1y-11-keto-12-bomo-24,24-

(31). 5.80 g. (0.0092 mole) of crude 3(a)-acet0xy-11-keto-12- bromo-24,24-diphenyl-A -choladiene (M. P. I'll-172) was dissolved in 37 ml. of alcoholfree chloroform and 55 ml. of glacial acetic acid and 9.2 ml. of water was added. The solution was cooled to 10 and 19.6 ml. of 8.5 N chromic acid (18 equiv.) in 85 per cent acetic acidper cent water was added while the solution was being stirred vigorously. The temperature rose to 15. After fifteen minutes the temperature had fallen to 10 and 16.6 ml. of 10 N sulfuric acid (18 equiv.) was added. The reaction mixture was then stirred 105 minutes at 10-15, diluted with a large volume of water and extracted with 3 portions of chloroform. The chloroform solution was washed with water and evaporated-to dryness in vacuo. The residue was dissolved in ether and a mixture of ice and aqueous'potassium hydroxide was added. A crop of fine crystals formed. Benzene was added and part of the crystalline material dissolved. The solution was filtered and the aqueous phase Was acidified with hydrochloric acid. (The acidic fraction weighed 148 mg.) The organic phase was washed with water, filteredthrough sodium sulfate, concentrated to a Yield: 2.226 g.=53 per cent; M P. 187-1882 0.436 g.=10.5 per cent; M. P. 186.5-188".

3 (a) -qcetoaiy-11,20-dilcetopregnane (36) from 3(a) -acetoa:y-11,20 diketo 12 bromopregmme (32) .-453 mg. (0.001 mole) of 3(a) -acetoxy-11,-

, 20-diketo-12-bromopregnane (M. P. 187-188) wasdissolved in 20 ml. of glacial acetic acid, 1 g. of powdered zinc was added and the reaction mixture was heated on the steam bath 15 minutes. The zinc was removed by filtration and the filtrate was evaporated to dryness in vacuo. The residue was distributed between water and benzene and the solution was washed with water. The benzene solution was filtered through sodium sulfate, concentrated in vacuo to a small volume and diluted with petroleum ether (B. P. -70). Crystals formed. Yield: mg., M. P. 132-134; 162 mg., M. P. 133-135". The product did not depress the melting point of 3(a)acetoxy-11,20- diketopregnane.

It has also been found that the conversion of 3,9-epoxy-l1-keto-24,24 diphenyl A23 cholene into 3(a) -acyloxy-11-keto-12-bromo 24,24 diphenyl-A -ch0lenes may be even more effectively carried out by treating the epoxy compound with dry hydrogen bromide in non-acylating solvents, such as chloroform alone, and thereafter converting the 3(a)-hydroxy-11-keto-12-bromo-24,24

dlphenyl-A l-choleneinto the desired 3(a)-acyl-' oxy derivative by treatment. with an acylating' Dry Ice-acetone bath. and g. of dry hydrogen bromide was introduced. The flask was sealed .at'Dry Ice temperature and then placed in an ice bath for 48 hours. The flask was cooled in a Dry Ice-acetone bath and the solution was poured onto chipped ice. Chloroform was added, the aqueous phase was separated and the organic phase was washed with water, sodium carbonate, and again with water. The chloroform solution was filtered through sodium sulfate, concentrated in vacuo to a small volume and the last traces of chloroform were displaced with acetic anhydride. The acetic anhydride solution was boiled for four hours and cooled. The crystals of the 3(a) acetoxy compound (29) which formed were filtered and washed with acetic anhydride.

I claim:

1. 3(a)-acetoxy-11-keto-12-bromo 24,24 diphenyl-A -choladiene.

2. Process for the production of 3(a) -acyloxy- 11-keto-12-bromo-24,24-diphenyl-A choladiene which comprises reacting 3,9-epoxy-11- keto-24,24-diphenyl-A 3-cholene with hydrogen bromide, converting the resulting 3(a)-hydroxyll-keto-12-bromo-24,24-diphenyl-A -cholene into the corresponding 3(a)-acyloxy derivative by treatment with an acylatingagent, and reacting the 3(a)-acyloxy compound with N'-bromosuccinimide to produce 3()-acyloxy-11-keto-12- bromo-24,24-diphenyl-A -choladiene.

3. Process for the production of 3(a) -acetoxyl1-keto-12-bromo-24,24-diphenyl-A choladiene which comprises reacting 3,9-epoxy-11- keto-24,24-diphenyl-A -cholene with hydrogen bromide, converting the resulting 3(a) -hydroxy- 11-keto-12-bromo-24,24-diphenyl-A -cholene into the corresponding 3(a)-acetoxy derivative by treatment with acetic anhydride, and reacting the 3(a)-acetoxy compound with N-bromosuccinimide to produce 3(a) -acetoxy-11-keto-12-bromo- 24,24-diphenyl-A -choladiene.

4. Process for the preparation of 3 (a) -acetoxy- 11-keto-l2-bromo-24,24-diphenyl-A choladiene which comprises reacting 3,9-epoxy-11- keto-24,24-diphenyl-A -cholene with hydro en bromide in the presence of acetic anhydride and reacting the resulting 3(a) -acetoxy-11-keto-12- bromo-24,24-diphenyl-A -ch0lene with N-bromosuccinimide.

5. 3(a) -acetoxy-11-keto-12-bromo 24,24 diphenyl-A -cholene.

6. The step in the process of making 3(a)- acyloxy-11-keto-12-bromo-24,24 diphenyl A cholenes which comprises reacting 3,9-epoxy-11- keto-24,24-diphenyl n cholene with hydrogen bromide.

'7. The method for producing 3(a) -acyloxy-1lketo-12 bromo 24,24 diphenyl A cholenes which comprises reacting 3,9-epoxy-ll-keto-24,- 24-diphenyl-A -cholene with hydrogen bromide and. .reacting the 3(a) -hydroxy-l'.l-keto -l2- 6 pheny1-A -cho1ene with hydrogen bromide in the presence of acetic anhydride.

EDWARD C. KENDALL.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Miescher Feb. 15, 1949 Number 

1. 3(A)-ACETOXY-11-KETO-12-BROMO-24,24-DI PHENYL-$20:22,23:24-CHOLADIENE. 